1.AbstractTo address the current threat of antimalarial resistance, countries need innovative solutions for timely and informed decision-making. Integrating molecular resistance marker surveillance into routine malaria surveillance in pre-elimination contexts offers a potential early warning mechanism to identify resistance signals and target areas for further investigation, including therapeutic efficacy studies. However, there is limited evidence on what influences the performance of such a system in resource-limited settings.From March 2018 to February 2020, a sequential mixed-methods study was conducted in primary healthcare facilities in a South African pre-elimination setting to explore factors influencing the flow, quality and linkage of malaria case notification and antimalarial molecular resistance marker data. Using a process-oriented framework, we undertook monthly and quarterly data linkage and consistency analysis at different levels of the health system, as well as a survey, focus group discussions and interviews to identify potential barriers to, and enhancers of, the roll-out and uptake of this integrated information system.Over two years, 4,787 confirmed malaria cases were notified from 42 primary healthcare facilities in the Nkomazi sub-district, Mpumalanga, South Africa. Of the notified cases, 78.5% (n=3,758) were investigated, and 55.1% (n=2,636) were successfully linked to theirPlasmodium falciparummolecular resistance marker profiles. Five tangible processes—malaria case detection and notification, sample collection, case investigation, analysis and reporting—were identified within the process-oriented logic model. Workload, training, ease of use, supervision, leadership, and resources were recognized as cross-cutting influencers affecting the program’s performance.Approaching malaria elimination, linking molecular markers of antimalarial resistance to routine malaria surveillance is feasible. However, cross-cutting barriers inherent in the healthcare system can determine its success in a resource-limited setting.